A successful pregnancy and delivery require two distinct states of uterine activity: a quiescent state characterized by weak, asynchronous, regional contractions throughout pregnancy; and an activated state in which contractions increase in force, frequency, and synchrony to expel the fetus at term. These states are controlled by electrical activity of the uterine (myometrial) smooth muscle cells (MSMCs). Two key ions regulate MSMC electrical activity: calcium (Ca2+), which enters the cell, depolarizes the membrane, and activates the contractile machinery; and potassium (K+), which effluxes from the cell, repolarizes (inside of the membrane more negative than outside) the membrane, and returns the cell to the resting state. The traditional model is that Ca2+ enters through voltage-gated Ca2+ (Cav) channels and activates the large-conductance Ca2+-activated K+ channel KCa1.1. Here, we propose that whereas this model explains the basal, quiescent state, it is insufficient to explain the activated, inflammatory state characteristic of term labor. Instead, we propose a new model in which low KCa1.1 activity and Cav-mediated Ca2+ influx maintain MSMC membrane polarization in basal states, but high KCa1.1 activity and Ca2+ influx through store-operated Ca2+ (SOC) channels are required for membrane repolarization in inflammatory states. This new model is founded on several pieces of published and preliminary data. First, KCa1.1 is substantially more active in MSMCs isolated from laboring women than in those from non-laboring women. Second, when the inflammatory protein alpha-2- macroglobulin (?2M) binds to its receptor, low density lipoprotein receptor-related protein 1 (LRP1), KCa1.1 activity enhances Ca2+ oscillations in MSMCs. Third, these Ca2+ oscillations are not inhibited by the Cav blocker nifedipine, but by SOC inhibitors. Finally, in MSMCs, KCa1.1 interacts with ?2?1, the subunit that traffics Cav to the plasma membrane. To test our model, we will pursue three specific aims: 1) Determine the extent to which KCa1.1 is required for MSMC excitability in basal and inflammatory states; 2) Define the mechanism by which inflammatory stimuli enhance KCa1.1 and Ca2+ channel activity; and 3) Determine the mechanism by which KCa1.1 inhibits Cav-mediated Ca2+ influx. Insights gained from this work may lead to new therapeutic strategies to modulate uterine excitability and prevent aberrant uterine activity.